FIELD OF THE INVENTION

The present invention generally relates to agonists of the growth hormone releasing factor (GRF) receptor, and uses thereof. In particular, the present invention relates to GRF analogs, and uses thereof.

REFERENCE TO SEQUENCE LISTING

Pursuant to 37 C.F.R. 1.821(c), a sequence listing is submitted herewith as an ASCII compliant text file named “Sequence_Listing.txt” that was created on Apr. 17, 2012, and having a size of 26,866 bytes. The content of the aforementioned file named “Sequence Listing.txt” is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Growth hormone (GH) is produced in somatotroph cells of the anterior pituitary gland of mammals and secreted throughout life. It is mainly controlled in the brain by two hypothalamic peptides: GRF, which stimulates its secretion and synthesis; and somatostatin, which inhibits them. A number of peripheral factors regulate GH secretion. Among them, insulin-like growth factor-1 (IGF-1) represents an important one as it is produced by the liver in response to GH and acts on the hypothalamus to exert a negative feedback on GH secretion.

The decrease of GH secretion with age, demonstrated in humans and animals, favors a metabolic shift towards catabolism which initiates or participates in the aging of an organism. Loss of muscle mass, accumulation of adipose tissue, bone demineralization, and loss of tissue regeneration capacity after injury, which are observed in the elderly, correlate with the decrease in the secretion of GH.

GH is thus a physiological anabolic agent that is involved in the linear growth of children and which controls protein metabolism in adults.

GRF (also referred to as GH releasing hormone or GHRH) is a 44 amino acid peptide secreted by the hypothalamus that regulates the expression, synthesis and release of GH from the somatotroph cells of the anterior pituitary (Frohman L A et al. Endocrine Reviews 1986, 7: 223-253). A peptide consisting of the first 29 amino acids of human GRF (hGRF(1-29); sermorelin) retains the biological activity of the full-length peptide (Lance, V. A. et al., Biochemical and Biophysical Research Communications 1984, 119: 265-272) and has been used clinically for the treatment of GH deficiency in children (Thorner, M. et al., Journal of Clinical Endocrinology and Metabolism 1996, 81: 1189-1196). More recently, the potential of GRF to reverse the age-related decline in the function of the somatotrophic GH-insulin-like growth factor (IGF)-I axis has been evaluated (Khorram, O. et al., Clinical Obstetrics and Gynecology 2001, 44: 893-901).

A pharmaceutical preparation of hGRF(1-29) has been available for clinical use (Geref®, Laboratoires Serono S.A.). However, its pharmacological value is limited by its short half-life (approximately 12 min. following intravenous injection in humans), mainly due its susceptibility to rapid enzymatic degradation (Frohman, L. A. et al., Journal of Clinical Investigation 1986, 78: 906-913).

There is thus a need for the development of novel GRF analogs exhibiting agonist properties toward the GRF receptor or GHRH receptor (GHRHr).

The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.

X1 is Tyr or His; X2 is Ala, D-Ala, Ser, Leu, α-aminoisobutyric acid (Aib), Val or Gly; X8 is Asn, Asp, Ala, Gln, Ser or Aib; X9 is Ser, Asp or Ala; X11 is Arg or L-Homoarginine; X12 is Lys, L-Ornithine or L-Homoarginine; X13 is Val or Ile; X15 is Gly or Ala; X18 is Lys, L-Ornithine, L-2,4-diaminobutyric acid, L-2,3-diaminopropionic acid or Ser; X19 is Ala or Leu X22 is Asp or Glu; X23 is Ile or Leu; X24 is Met, Ile, Nle or Leu; X25 is Ser, Asn, Aib or Ala; X26 is Arg, D-Arg, L-Homoarginine or Lys; X27 is Ala or is absent; X28 is Ala or is absent; X29 is Arg or is absent; X30 is Ala or is absent; X31 is Ala or is absent; X32 is Arg or is absent; X33 is HoSer or is absent;

and wherein if X18 is Ser, X27 to X32 or X27 to X33 are present,

or a pharmaceutically acceptable salt thereof.

In an embodiment, X1 is Tyr. In an embodiment, X2 is Ala or D-Ala. In an embodiment, X8 is Ala or Asp, in a further embodiment Asp. In an embodiment, X9 is Ser. In an embodiment, X11 is Arg. In an embodiment, X12 is Lys or L-Homoarginine, in a further embodiment Lys. In an embodiment, X15 is Ala. In an embodiment, X18 is L-Ornithine or Lys, in a further embodiment Lys. In an embodiment, X22 is Asp. In an embodiment, X23 is Ile. In an embodiment, X24 is Leu. In an embodiment, X25 is Ala or Ser, in a further embodiment Ala. In an embodiment, X26 is Arg or D-Arg, in a further embodiment Arg. In an embodiment, X27 is Ala. In an embodiment, X28 is Ala. In an embodiment, X29 is Arg. In an embodiment, X30 is Ala. In an embodiment, X31 is Ala. In an embodiment, X32 is Arg. In an embodiment X33 is HoSer.

In another embodiment, at least one of X27 to X33 is/are absent. In a further embodiment, X27 to X33 are absent.

In an embodiment, the above-mentioned GRF analog further comprises (i) an amino-terminal modifying group; (ii) a carboxy-terminal modifying group; or (iii) both (i) and (ii).

In a further embodiment, the above-mentioned amino-terminal modifying group is a linear or branched saturated C1-C6 acyl group or unsaturated C3-C6 acyl group. In yet a further embodiment, the above-mentioned amino-terminal modifying group is an acetyl group (Ac). In another embodiment, the above-mentioned amino-terminal modifying group is a trans-3-hexenoyl group.

In a further embodiment, the above-mentioned carboxy-terminal modifying group is NH2.

In a further embodiment, the above-mentioned GRF analog is Y-a-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-I-L-A-R-A-A-R-A-A-R-NH2 (SEQ ID NO: 28).

In another further embodiment, the above-mentioned GRF analog is Y-a-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-L-R-Q-D-I-L-A-R-A-A-R-A-A-R-NH2 (SEQ ID NO: 29).

In another further embodiment, the above-mentioned GRF analog is Y-a-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-L-L-A-R-A-A-R-A-A-R-NH2 (SEQ ID NO: 30).

In another further embodiment, the above-mentioned GRF analog is trans-3-hexenoyl-Y-A-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-I-L-A-R-A-A-R-A-A-R-NH2 (SEQ ID NO: 31).

In another further embodiment, the above-mentioned GRF analog is trans-3-hexenoyl-Y-A-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-L-L-A-R-A-A-R-A-A-R-NH2 (SEQ ID NO: 32).

In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned GRF analog.

In an embodiment, the above-mentioned pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

In an aspect, the present invention provides a method for inducing growth hormone secretion in a subject in need thereof, said method comprising administering to said subject an effective amount of the above-mentioned GRF analog or pharmaceutical composition.

In another aspect, the present invention provides a use of the above-mentioned GRF analog or pharmaceutical composition, for inducing growth hormone secretion in a subject.

In another aspect, the present invention provides a use of the above-mentioned GRF analog or pharmaceutical composition, for the preparation of a medicament for inducing growth hormone secretion in a subject.

In another aspect, the present invention provides the above-mentioned GRF analog or pharmaceutical composition, for the preparation of a medicament for inducing growth hormone secretion in a subject.

In another aspect, the present invention provides the above-mentioned GRF analog or pharmaceutical composition, for inducing growth hormone secretion in a subject.

In another aspect, the present invention provides a use of the above-mentioned GRF analog or pharmaceutical composition, as a medicament.

In another aspect, the present invention provides the above-mentioned GRF analog or pharmaceutical composition, for use as a medicament.

In an embodiment, the above-mentioned GRF analog is administered or is adapted for administration at a daily dose of about 0.1 mg to about 20 mg.

In embodiments, the above-mentioned GRF analog is administered, or is adapted for administration, intravenously, orally, transdermally, subcutaneously, mucosally, intramuscularly, intranasally, intrapulmonary, parenterally, intrarectally or topically, in further embodiments subcutaneously or transdermally.

Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present inventors have discovered novel GRF analogs that exhibit an agonistic activity on cells expressing the GHRHr, and induce GH secretion in animal models.

Native human GRF is a peptide of 44 amino acids having the following structure: Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu (SEQ ID NO:38).

The 29 amino acid N-terminal fragment of GRF(1-44), known as GRF(1-29), has been shown to exhibit biological activity and potency that is similar to GRF(1-44). GRF(1-29) has the following sequence: Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg (SEQ ID NO:39).

Intermediates forms (in length) between GRF(1-29) and GRF(1-44), i.e., having the sequence of GRF(1-29) at the C-terminus of which 1-14 amino acids are added which correspond to residues 30-43 of native human GRF (or other residues), also possess GRF activity. Further, certain GRF variants having one or more amino acid substitutions in the native sequence are known to possess GRF activity.

The GRF analogs of the present invention are variants of GRF and active fragments and/or variants thereof, comprising a 3 amino acid residue deletion at positions corresponding to residues 21 to 23 (Lys-Leu-Leu underlined in the sequences depicted above) of the native human GRF(1-44), its N-terminal fragment GRF(1-29), or the intermediate forms noted above. The GRF analog of the invention may further comprise an alteration of the serine corresponding to position 18 (in italics in the sequences depicted above), preferably a substitution with Lys, L-Ornithine, L-2,4-diaminobutyric acid or L-2,3-diaminopropionic acid, of the native human GRF(1-44), its N-terminal fragment GRF(1-29), or the intermediate forms noted above. These GRF analogs exhibit agonistic activity on cells expressing the GHRHr, and induce GH secretion in animal models.

The terms “GRF analog”, “GRF receptor agonist”, “GRF peptide”, “GRF peptide compound” or “peptide compound” are used interchangeably herein to refer to the compounds of the present invention that exhibit an agonistic activity on cells expressing the GHRHr and induce GH secretion in animal models, which are described in further detail below. The terms “GRF” (growth hormone-releasing factor) and “GHRH” (growth hormone-releasing hormone) are used interchangeably herein. Similarly, the terms “GRF receptor”, “GRFr”, “GHRH receptor” and “GHRHr” are used interchangeably herein.

wherein: X1 is Tyr or His; X2 is Ala, D-Ala, Ser, Leu, α-aminoisobutyric acid (Aib), Val or Gly; X8 is Asn, Asp, Ala, Gln, Ser or Aib; X9 is Ser, Asp or Ala; X11 is Arg or L-Homoarginine; X12 is Lys, L-Ornithine or L-Homoarginine; X13 is Val or Ile; X15 is Gly or Ala; X18 is Lys, L-Ornithine, L-2,4-diaminobutyric acid, L-2,3-diaminopropionic acid or Ser; X19 is Ala or Leu X22 is Asp or Glu; X23 is Ile or Leu; X24 is Met, Ile, Nle or Leu; X25 is Ser, Asn, Aib or Ala; X26 is Arg, D-Arg, L-Homoarginine or Lys; X27 is Ala or is absent; X28 is Ala or is absent; X29 is Arg or is absent; X30 is Ala or is absent; X31 is Ala or is absent; X32 is Arg or is absent; X33 is HoSer or is absent;

and wherein if X18 is Ser, X27 to X32 or X27 to X33 are present, or a pharmaceutically acceptable salt thereof.

wherein: X1 is any amino acid, in an embodiment Tyr or His, in a further embodiment Tyr; X2 is any amino acid, in an embodiment Ala, D-Ala, Ser, Leu, α-aminoisobutyric acid (Aib), Val or Gly, in a further embodiment Ala or D-Ala; X8 is any amino acid, in an embodiment Asn, Asp, Ala, Gln, Ser or Aib, in a further embodiment Ala or Asp, in a further embodiment Asp; X9 is any amino acid, in an embodiment Ser, Asp or Ala, in a further embodiment Ser; X11 is any amino acid, in an embodiment Arg or L-Homoarginine, in a further embodiment Arg; X12 is any amino acid, in an embodiment Lys, L-Ornithine or L-homoarginine, in a further embodiment Lys or L-homoarginine, in yet a further embodiment Lys; X13 is any amino acid, in an embodiment Val or Ala, in a further embodiment Val; X15 is any amino acid, in an embodiment Gly or Ala, in a further embodiment Ala; X18 is any amino acid, in an embodiment Lys, L-Ornithine, L-2,4-diaminobutyric acid or L-2,3-diaminopropionic acid, in a further embodiment Lys or L-Ornithine, in yet a further embodiment Lys; X19 is Ala or Leu; X22 is any amino acid, in an embodiment Asp or Glu, in a further embodiment Asp; X23 is any amino acid, in an embodiment Ile or Leu, in a further embodiment Ile; X24 is any amino acid, in an embodiment Met, Ile, Nle or Leu, in a further embodiment Met or Leu, in a further embodiment Leu; X25 is any amino acid, in an embodiment Ser, Asn, Aib or Ala, in a further embodiment Ala or Ser, in yet a further embodiment Ala; X26 is any amino acid, in an embodiment Arg, D-Arg, L-Homoarginine or Lys, in a further embodiment Arg or D-Arg, in yet a further embodiment Arg; X27 is any amino acid, in an embodiment Ala, or is absent; X28 is any amino acid, in an embodiment Ala, or is absent; X29 is any amino acid, in an embodiment Arg, or is absent; X30 is any amino acid, in an embodiment Ala, or is absent; X31 is any amino acid, in an embodiment Ala or is absent; X32 is any amino acid, in an embodiment Arg, or is absent; and X33 is any amino acid, in an embodiment HoSer, or is absent;

and wherein if X18 is Ser, X27 to X32 or X27 to X33 are present, or a pharmaceutically acceptable salt thereof.

The term “amino acid” as used herein includes both L- and D-isomers of the naturally occurring amino acids as well as other amino acids (e.g., naturally-occurring amino acids, non-naturally-occurring amino acids, amino acids which are not encoded by nucleic acid sequences, etc.) used in peptide chemistry to prepare synthetic analogs of peptides. Examples of naturally-occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, etc.

In embodiments, domains or GRF analogs of the present invention include polypeptides with altered sequences containing substitutions of functionally equivalent amino acid residues, relative to the above-mentioned domains or GRF analogs. For example, one or more amino acid residues within the sequence can be substituted by another amino acid of a similar polarity (having similar physico-chemical properties) which acts as a functional equivalent, resulting in a silent alteration. Substitution for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs. For example, positively charged (basic) amino acids include arginine, lysine and histidine (as well as homoarginine and ornithine). Nonpolar (hydrophobic) amino acids include leucine, isoleucine, alanine, phenylalanine, valine, proline, tryptophan and methionine. Uncharged polar amino acids include serine, threonine, cysteine, tyrosine, asparagine and glutamine. Negatively charged (acidic) amino acids include glutamic acid and aspartic acid. The amino acid glycine may be included in either the nonpolar amino acid family or the uncharged (neutral) polar amino acid family. Substitutions made within a family of amino acids are generally understood to be conservative substitutions.

The above-mentioned domain or GRF analog may comprise all L-amino acids, all D-amino acids or a mixture of L- and D-amino acids. In an embodiment, the above-mentioned domain or GRF analog comprises at least one D-amino acid (e.g., 1, 2, 3, 4, 5 or more D-amino acids). In an embodiment, the above-mentioned domain or GRF analog comprises at least one D-Ala and/or D-Arg residue. In an embodiment, said at least one D-amino acid is located in the N-terminal and/or C-terminal portion of the domain or GRF analog (e.g., within the last 2 or 3 N- and/or C-terminal residues). The presence of one or more D-amino acids typically results in peptides having increased stability (e.g., in vivo) due to decreased susceptibility to protease/peptidase cleavage, but which retain biological activity.

In embodiments, the above-mentioned GRF analog is in the form of a salt, e.g., a pharmaceutically acceptable salt. As used herein the term “pharmaceutically acceptable salt” refers to salts of compounds that retain the biological activity of the parent compound, and which are not biologically or otherwise undesirable. Such salts can be prepared in situ during the final isolation and purification of the analog, or may be prepared separately by reacting a free base function with a suitable acid. Many of the GRF analogs disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

Basic addition salts also can be prepared by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium, amongst others. Other representative organic amines useful for the formation of base addition salts include, for example, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines.

In an embodiment, in formula (I) and/or (II), X30 to X32 are absent. In another embodiment, X30 to X33 are absent.

In an embodiment, in formula (I) and/or (II), X27 to X29 are as follows: Ala-Ala-Arg.

In another embodiment, in formula (I) and/or (II), X27 to X32 are absent. In another embodiment, X27 to X33 are absent.

In another embodiment, in formula (I) and/or (II), X18 is Lys and X27 to X29, X27 to X32 or X27 to X33 are present. In an embodiment, X27 to X32 are as follows: Ala-Ala-Arg-Ala-Ala-Arg (SEQ ID NO: 41). In an embodiment, X27 to X33 are as follows: Ala-Ala-Arg-Ala-Ala-Arg-HoSer (SEQ ID NO: 42).

In an embodiment, the above-mentioned GRF analog comprises one domain of formula I or II as defined above. In an embodiment, the above-mentioned GRF analog comprises two or more (e.g., 2, 3, 4 or 5) domains of formula I or II as defined above.

In embodiments, the above-mentioned GRF analog may comprise, further to the domain of formula I or II defined above, one more amino acids (naturally occurring or synthetic) covalently linked to the amino- and/or carboxy-termini of said domain. In an embodiment, the above-mentioned GRF analog comprises up to 25 additional amino acids at the N- and/or C-termini to the domain of formula (I) or (II) defined above. In further embodiments, the above-mentioned GRF analog comprises up to 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 additional amino acids at the N- and/or C-termini of the domain of formula (I) or (II) defined above. In an embodiment, the above-mentioned domain or GRF analog contains about 100 residues or less, in further embodiments about 90, 80, 70, 60, 50, 40 or 35 residues or less. In an embodiment, the above-mentioned domain or GRF analog contains between about 26 residues to about 100 residues. In a further embodiment, the above-mentioned domain or GRF analog contains between about 26 residues to about 50 residues. In a further embodiment, the above-mentioned GRF analog contains between about 26 residues to about 45 residues. In a further embodiment, the above-mentioned GRF analog contains between about 26 residues to about 40 residues. In a further embodiment, the above-mentioned GRF analog contains about 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 or 39 residues.

In an embodiment, the above-mentioned domain or GRF analog is a peptidomimetic. A peptidomimetic is typically characterised by retaining the polarity, three dimensional size and functionality (bioactivity) of its peptide equivalent, but wherein one or more of the peptide bonds/linkages have been replaced, often by more stable linkages. Generally, the bond which replaces the amide bond (amide bond surrogate) conserves many or all of the properties of the amide bond, e.g. conformation, steric bulk, electrostatic character, potential for hydrogen bonding, etc. Typical peptide bond replacements include esters, polyamines and derivatives thereof as well as substituted alkanes and alkenes, such as aminomethyl and ketomethylene. For example, the above-mentioned domain or GRF analog may have one or more peptide linkages replaced by linkages such as —CH2NH—, —CH2S—, —CH2—CH2—, —CH═CH— (cis or trans), —CH2SO—, —CH(OH)CH2—, or —COCH2—. Such peptidomimetics may have greater chemical stability, enhanced biological/pharmacological properties (e.g., half-life, absorption, potency, efficiency, etc.) and/or reduced antigenicity relative its peptide equivalent.

In embodiments, the GRF analog consists of the domain of formula (I) or (II) defined above.

In a further embodiment, the above-mentioned domain is Y-A-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-I-L-A-R-A-A-R (SEQ ID NO: 8).

In a further embodiment, the above-mentioned domain is Y-A-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-S-A-R-Q-D-I-L-A-R-A-A-R-A-A-R (SEQ ID NO: 9).

In a further embodiment, the above-mentioned domain is Y-a-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-I-L-A-R-A-A-R-A-A-R (SEQ ID NO: 10), wherein a=D-Ala.

In a further embodiment, the above-mentioned domain is Y-a-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-L-R-Q-D-I-L-A-R-A-A-R-A-A-R (SEQ ID NO: 11), wherein a=D-Ala.

In a further embodiment, the above-mentioned domain is Y-a-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-L-L-A-R-A-A-R-A-A-R (SEQ ID NO: 12), wherein a=D-Ala.

In a further embodiment, the above-mentioned domain is Y-A-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-I-L-A-R-A-A-R-A-A-R (SEQ ID NO: 13).

In a further embodiment, the above-mentioned domain is Y-A-D-A-I-F-T-D-S-Y-R-K-V-L-A-Q-L-K-A-R-Q-D-L-L-A-R-A-A-R-A-A-R (SEQ ID NO: 14).

In embodiments, the N- and/or C-terminal amino acids of the above-mentioned GRF analog or domain may be modified, for example by amidation, acetylation, acylation or any other modifications known in the art.

Accordingly, in another aspect, the present invention provides a GRF analog of formula (III):

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